Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/60—Salicylic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to pharmaceutical compositions having antiphlogistic, antipyretic and analgesic activity. More specifically, the present invention relates to compositions having as the active component imidazole salicylate of chemical formula (I). ##STR2##
• the compound of formula (I) is known in the art but the pharmacological activity has not been described. It has now been found surprisingly that the compound exhibits very significant antiphlogistic, antipyretic and analgesic activity.
• compositions containing derivatives of salicylic acid and exhibiting antiphlogistic activity are well known. These compositions have the disadvantages that, in animals as well as in humans, particularly on repeated administration, they cause gastroenteric lesions which obviously limit substantially their therapeutic use. This side effect appears to be connected with the mechanism of antiphlogistic activity.
• imidazole salicylate of formula (I) exhibits the same activity described hereinabove without exhibiting the side effects of gastroenteric lesions. This constitutes a clear and substantial therapeutic improvement with respect to the known pharmaceutical compositions.
• the several pharmacotoxicological properties of the compound of formula (I) are more advantageous when compared to the properties of salicyclic acid and of imidazole when they are administered separately. More specifically, imidazole salicylate exhibits a greater antiphlogistic activity and a superior tolerability on a gastroenteric level when compared to salicylic acid and to salts of salicylic acids with inorganic cations.
• Salicylic acid one mole (138.128 grams), and one mole of imidazole (68.088 grams) are dissolved in 700 cc of analytically pure methanol. The mixture is allowed to stand overnight. The solution is then evaporated at atmospheric pressure to a volume of 200 cc at which point, under stirring, the material crystallizes. The solution is redissolved in about 300 cc of boiling methanol and the solution is evaporated to a volume of about 250 cc. After crystallization has begun, diethyl ether in the amount of 50 cc, is added and the mixture is allowed to stand at a temperature of -20° C. The solid which is formed is filtered off and washed with a small amount of cold methanol and ether.
• the material obtained amounts to 150 grams of wet product.
• the product is recrystallized from a mixture of methanol and ether, thus obtaining 110 grams of material.
• An additional amount of 69 grams of crystalline material is obtained from the mother liquor by evaporation and crystallization from methanol and ether.
• Imidazole salicylate is referred to hereinbelow with the symbol SZ.
• the DL 50 in mice after a single administration by the oral route in animals of both sexes is 1109 mg/kg of body weight.
• the DL 50 of sodium salicylate is 1600 mg/kg. and in the case of imidazole it is 880 mg/kg. Therefore, the acute toxicity of SZ is intermediate between the value of sodium salicylate and imidazole and it is closer to the DL 50 of acetylsalicylic acid.
• the DL 50 determined experimentally for imidazole is very close to the value reported by Puig Muset P. et al, Biochemical and Pharmacological Aspects of Imidazole, P.E.V.Y.F., Barcellona 1972 which is 885 mg/kg of body weight.
• the sub-acute toxicity has been tested in Wistar rats during the growth phase by daily administration of doses of 50, 100 and 200 mg/kg, by administering every day of the week to groups of ten (10) animals the substance by the gastric tube.
• the activity is demonstrated to be in a dosage of between 50 and 200 mg/kg/os.
• the DE 50 is 150 mg/kg/os (L.F. 50-200).
• imidazole in a dosage between 33-99 mg/kg/os is inactive and sodium salicylate has a DE 50 of about 240 mg/kg/os.
• acetylsalicylic acid tested by us in a dose of 50-200 mg/kg/os has given inhibition of 50-80%.
• the antiphlogistic activity of the substance results, therefore, in the range of the activity of acetylsalicylic acid and is superior to the activity of sodium salicylate.
• the substance SZ therefore, exhibits antipyretic activity superior to acetylsalicylic acid.
• the compound SZ in the dosage required to exert antithermic, antiphlogistic and analgesic activity has no effect on the behavior, motor function and vegetative functions of the animal tested. Only in the dosage of 200 mg/kg/os one notes an increase in the spontaneous motility.
• the ulcerogenic activity of the substance SZ (estimated as increments of the gravity of the ulcerogenic situation of the non-treated controls has resulted to be substantially lower than that obtained from an equimolar dose of sodium salicylate or aspirin, as far as the number of ulcers in a stomach, the total number of ulcers and the number of bleeding ulcers.
• the substance SZ has not exhibited any mutagenic activity with or without metabolic activation.
• the substance SZ exhibits a specific antipyretic and antiphlogistic activity which is equivalent to the activity of acetylsalicylic acid, but the ulcerogenic activity is substantially lower and the inhibitory action with respect to the biosynthesis of prostaglandin is substantially lower.
• the substance may be administered in the form of tablets, capsules, pills, in solutions or suspension, with inert carriers.
• a suitable dose is:

Landscapes

• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pain & Pain Management (AREA)
• Epidemiology (AREA)
• Rheumatology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

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• 1980
  • 1980-08-05 IT IT23998/80A patent/IT1194677B/it active Protection Beyond IP Right Term
  • 1980-12-08 US US06/214,204 patent/US4329340A/en not_active Expired - Lifetime
  • 1980-12-09 DE DE3046325A patent/DE3046325C2/de not_active Expired
• 1981
  • 1981-07-06 CH CH4423/81A patent/CH652305A5/it not_active IP Right Cessation
  • 1981-07-06 FI FI812131A patent/FI812131L/fi not_active Application Discontinuation
  • 1981-07-06 NO NO812304A patent/NO812304L/no unknown
  • 1981-07-08 AU AU72669/81A patent/AU550428B2/en not_active Ceased
  • 1981-07-09 PH PH25880A patent/PH16837A/en unknown
  • 1981-07-10 AR AR286037A patent/AR225226A1/es active
  • 1981-07-13 GB GB8121509A patent/GB2081093B/en not_active Expired
  • 1981-07-14 ZA ZA814800A patent/ZA814800B/xx unknown
  • 1981-07-15 DK DK314681A patent/DK314681A/da not_active Application Discontinuation
  • 1981-07-23 NL NL8103501A patent/NL8103501A/nl not_active Application Discontinuation
  • 1981-07-23 BE BE2/59273A patent/BE889704A/nl not_active IP Right Cessation
  • 1981-07-28 CA CA000382685A patent/CA1177755A/en not_active Expired
  • 1981-07-29 JP JP56119992A patent/JPS6148808B2/ja not_active Expired
  • 1981-08-03 LU LU83530A patent/LU83530A1/de unknown
  • 1981-08-03 FR FR8115052A patent/FR2488136A1/fr active Granted
  • 1981-08-03 GR GR65701A patent/GR75304B/el unknown
  • 1981-08-04 SE SE8104675A patent/SE455572B/sv not_active IP Right Cessation
  • 1981-08-04 IE IE1773/81A patent/IE51465B1/en not_active IP Right Cessation
  • 1981-08-04 ES ES504523A patent/ES8304059A1/es not_active Expired
  • 1981-08-04 BR BR8105020A patent/BR8105020A/pt unknown
  • 1981-08-04 PT PT73480A patent/PT73480B/pt not_active IP Right Cessation
  • 1981-08-04 MX MX819590U patent/MX6968E/es unknown
• 1992
  • 1992-06-23 MX MX9203174A patent/MX9203174A/es not_active Application Discontinuation

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